ABSTRACT Hepatocellular carcinoma (HCC) and chronic liver diseases (CLD) and are significant health problems in the United States affecting racial/ethnic minorities disproportionately. In the Multiethnic Cohort (MEC) Study, a long- standing ethnically diverse prospective cohort (>200,000 participants), we observed striking ethnic differences in HCC incidence with Latinos having the highest incidence followed by Native Hawaiians, African Americans, Japanese Americans, and whites. US-born Latinos, particularly men, experience the highest rates of HCC incidence in the cohort. We also found nonalcoholic fatty liver disease (NAFLD) to be the most common cause of CLD and an unexpectedly high NALFD prevalence in Japanese Americans and Native Hawaiians. These findings provide the groundwork for studies to elucidate the factors that account for health disparities across these populations. To date, no liver disease studies have included Japanese Americans and Native Hawaiians; thus, a large knowledge gap remains in understanding the factors underlying disparities in HCC and NALFD in these understudied high-risk populations. The MEC with its comprehensive lifestyle, environmental, and genetic data offers a unique opportunity to elucidate the determinants that account for these health disparities. In this study we will examine the association of lifestyle, genetic, social, and contextual factors with HCC and NAFLD among MEC participants to better understand disease etiology in high-risk minorities and the factors underlying ethnic disparities. We will use existing resources of the MEC with detailed demographic, lifestyle, neighborhood- level data, health condition data, and cancer incidence and mortality information from SEER Cancer registries and state and national mortality databases, as well as a large biorepository of blood samples. These data have been collected in a consistent fashion amongst all MEC participants to permit valid ethnic comparisons. Our specific aims are 1) To quantify the contribution of known risk factors (chronic hepatitis C and B, adiposity, metabolic syndrome, alcohol intake and tobacco smoking) to ethnic differences in HCC incidence and identify additional risk factors (lifestyle and social/contextual factors) explaining the remaining ethnic variation in HCC incidence which would suggest novel or ethnic-specific mechanisms; 2) To evaluate ethnic-specific lifestyle, social and contextual factors and genetic factors that are associated with NAFLD across five ethnic groups and quantify their contributions to racial/ethnic differences in NALFD risk. Upon completion of this study, we will improve understanding of risk factors most important in certain ethnic groups and factors underlying disparities in HCC and NAFLD. The identification and defining the contribution of risk factors to racial/ethnic differences in HCC and NAFLD will be paramount for improving strategies for primary prevention of these diseases.